Co-occurrence of targetable mutations in Non-small cell lung cancer (NSCLC) patients harboring MAP2K1 mutations

Abstract

Background: MAP2K1 mutations are rare in non-small cell lung cancer (NSCLC) and considered to be mutually exclusive from known driver mutations. Activation of the MEK1-cascade is considered pivotal in resistance to targeted therapy approaches, and MAP2K1 K57 N mutation could be linked to resistance in preclinical models. We set out this study to detect MAP2K1 mutations and potentially targetable co-mutations using a molecular multiplex approach. Methods: Between 2012 and 2018, we routinely analyzed 14.512 NSCLC patients with two next-generation sequencing (NGS) panels. In a subset of patients, fluorescence in-situ hybridization was performed to detect rearrangements or amplifications. We assessed clinical parameters and co-occurring mutations and compared treatment outcomes of different forms of systemic therapy. Results: We identified 66 (0.5%) patients with MAP2K1 mutations. Both adenocarcinoma (n = 62) and squamous cell carcinoma (n = 4) histology. The presence of the mutations was linked to smoking, and transversions were more common than transitions. K57 N was the most frequent MAP2K1 mutation (n = 25). Additional mutations were found in 57 patients (86.4%). Mutations of TP53 were detected in 33 patients, followed by KEAP1 mutations in 28.1%. 24 patients (36.4%) had either MAP2K1-only or a co-occurring aberration considered targetable, including EGFR mutations, a BRAF V600E mutation and ROS1 rearrangements. Outcome analyses revealed a trend toward benefit from pemetrexed treatment. Conclusion: Our analysis shows that MAP2K1-mutated NSCLC patients might frequently present with potentially targetable aberrations. Their role in providing resistance in these subtypes and the possible therapeutic opportunities justify further analyses of this rare NSCLC subgroup.

Identification of common microRNA between COPD and non-small cell lung cancer through pathway enrichment analysis

“…D. Yang et al [44] stated that the expression level of miR-103, which we extracted as a common effective miRNA between both diseases mentioned, decreases in NSCLC and COPD tissues, while it inversely correlates with tumor stage and size. Moreover, miR-103 can prohibit cell proliferation, reduce tumor volume and weight, and increase apoptosis in NSCLC, while targeting MAP2K2 which is a member of MAPK signaling cascade and also a RAS downstream signaling pathway regulating cell proliferation, differentiation, and survival by ERK1/2 activation [45]. On the other hand, MAP2K2 as the downstream of proto-oncogene BRAF is also targeted by miR-17 which is up-regulated in NSCLC and COPD.…”

A Meta-Analysis Approach to Gene Regulatory Network Inference Identifies Key Regulators of Cardiovascular Diseases

“…In our analysis, Mitogen-Activated Protein Kinase 1 (MAP2K1) appears to be dysregulated in hypertrophic cardiomyopathy, leading to heart failure (Figure 5A). Mutations in this kinase have been associated with various types of tumors, such as lung cancer, melanoma, pancreatic cancer, and prostate cancer [78][79][80][81]. Specifically, mutations in RAF and RAS proteins cause improper activation of the MAPK signaling pathways, resulting in constitutive activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway.…”

Differential Gene Expression Analysis of Non-Small Cell Lung Cancer Samples to Classify Candidate Genes

“…MAP2K1 mutations are infrequent in NSCLC and are assumed to be mutually exclusive with known driver mutations. MEK1 cascade activation is believed to play a major role in the resistance to selective treatment regimens, and the MAP2K1 K57 N mutation has been associated with resistance in preclinical animals [26]. The fold change value for MAP2K1 and NRAS is greater than 1, indicating that these two genes are much more expressed than BRAF, KRAS, and EGFR.…”